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J. Biol. Chem., Vol. 282, Issue 30, 21746-21757, July 27, 2007

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Phospholipase D1 Production of Phosphatidic Acid at the Plasma Membrane Promotes Exocytosis of Large Dense-core Granules at a Late Stage^*

Maria Zeniou-Meyer, Naama Zabari, Uri Ashery, Sylvette Chasserot-Golaz, Anne-Marie Haeberlé, Valérie Demais^¶, Yannick Bailly, Irit Gottfried, Hideki Nakanishi^||, Aaron M. Neiman^||, Guangwei Du^**, Michael A. Frohman^**, Marie-France Bader, and Nicolas Vitale¹

From the Département Neurotransmission & Sécrétion Neuroendocrine, Institut des Neurosciences Cellulaires et Intégratives (UMR 7168/LC2), CNRS and Université Louis Pasteur, 5 rue Blaise Pascal, 67084 Strasbourg, France, the ^¶Plateforme Imagerie in Vitro, IFR37 des Neurosciences de Strasbourg, 5 rue Blaise Pascal, 67084 Strasbourg, France, the Department of Neurobiochemistry, Life Sciences Institute, Tel Aviv University, Tel Aviv 69978, Israel, and the Departments of ^||Biochemistry and ^**Pharmacology and the Center for Developmental Genetics, Stony Brook University, Stony Brook, New York 11794-5140

Substantial efforts have recently been made to demonstrate the importance of lipids and lipid-modifying enzymes in various membrane trafficking processes, including calcium-regulated exocytosis of hormones and neurotransmitters. Among bioactive lipids, phosphatidic acid (PA) is an attractive candidate to promote membrane fusion through its ability to change membrane topology. To date, however, the biosynthetic pathway, the dynamic location, and actual function of PA in secretory cells remain unknown. Using a short interference RNA strategy on chromaffin and PC12 cells, we demonstrate here that phospholipase D1 is activated in secretagogue-stimulated cells and that it produces PA at the plasma membrane at the secretory granule docking sites. We show that phospholipase D1 activation and PA production represent key events in the exocytotic progression. Membrane capacitance measurements indicate that reduction of endogenous PA impairs the formation of fusion-competent granules. Finally, we show that the PLD1 short interference RNA-mediated inhibition of exocytosis can be rescued by exogenous provision of a lipid that favors the transition of opposed bi-layer membranes to hemifused membranes having the outer leaflets fused. Our findings demonstrate that PA synthesis is required during exocytosis to facilitate a late event in the granule fusion pathway. We propose that the underlying mechanism is related to the ability of PA to alter membrane curvature and promote hemi-fusion.

Received for publication, April 9, 2007 , and in revised form, May 21, 2007.

^* This work was supported by the Agence Nationale de la Recherche (Grant ANR-05-BLAN-0326-01 to N. V.), by National Institutes of Health Grants GM071520 (to M. A. F.) and GM071475 (to G. D.), by the French Ministry of Science (Grant ACI-BCMS015 to M. F. B.), by the Fondation pour la Recherche Médicale (fellowship to M. Z. M.), by the Association pour la Recherche sur le Cancer (Grants 4051 and 5802 to N. V. and M. F. B., respectively), and by the Israel Science Foundation (Grant 912/06 to U. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and movie S1.

¹ To whom correspondence should be addressed. Tel.: 33-388-45-6712; Fax: 33-388-60-1664; E-mail: vitalen{at}neurochem.u-strasbg.fr.

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